Step 7. Collect Information About the Current R Session.

Contact - Centre for AIDD

Contact Us

The Centre for Artificial Intelligence Driven Drug Discovery (AIDD) at Macao Polytechnic University

Get in Touch

Location

匯智樓 (WUI CHI)-4/F, N46B
Rua de Luís Gonzaga Gomes
Macau

Email

kefengl@mpu.edu.mo

Phone

(+853) 8599 6883

Office Hours

Monday - Friday
10:00 AM - 4:00 PM

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Mediation Mendelian Randomization

Mediation Mendelian Randomization

Unraveling causal pathways: Understanding how exposures affect outcomes through mediating mechanisms using two-step MR analysis

The main purpose of mediation MR is to investigate whether a mediator can mediate the effect of exposure on the outcome. It is generally applicable for identifying potential mechanisms underlying the relationship from exposure to outcome.

Workflow Overview

Interactive Demo

Analysis Steps

1

Exposure → Outcome

Direct causal effect estimation.
Identify significant SNPs from exposure GWAS, remove LD, extract from outcome GWAS. Calculate total causal effect (β₀).

2

Exposure → Mediator

Exposure effect on mediator.
Use exposure SNPs to estimate causal effect on mediator, ensuring no direct confounder relationships. Calculate effect (β₁).

3

Mediator → Outcome

Mediator effect on outcome.
Identify mediator SNPs, remove LD, extract from outcome GWAS. Calculate mediator causal effect (β₂).

Results Interpretation

Effect Decomposition

Indirect Effect = β₁ × β₂
Direct Effect = β₀ - (β₁ × β₂)

Where β₀ is the total effect, β₁ is exposure→mediator effect, and β₂ is mediator→outcome effect.

Interpretation Scenarios:

Partial Mediation

If β₀, β₁, and β₂ are all significant: Causal association exists with partial mediation. Test if direct effect β₀ - (β₁ × β₂) significantly differs from 0.

Complete Mediation

If β₀ is not significant, but both β₁ and β₂ are significant: The association is entirely mediated by the mediator variable.

No Mediation

If β₀ is significant, but at least one of β₁ or β₂ is not significant: No mediating effect exists in the causal pathway.

Critical Considerations

Essential guidelines for responsible mediation MR analysis and interpretation

Methodological Rigor

While democratizing MR methodology is crucial, atheoretical applications pose significant risks. Avoid randomly selecting exposure-outcome pairs without biological justification or established hypotheses.

Best Practice: Ground analyses in well-defined, evidence-based hypotheses and adhere to established guidelines [1]. Consider biological plausibility, pleiotropic pathways, and implement comprehensive quality control including F-statistics evaluation and heterogeneity assessment.

1. Guidelines for performing Mendelian randomization investigations: update for summer 2023

Evidence Integration

MR results should never be interpreted in isolation. Robust causal inference requires integrating multiple analytical strategies and evidence sources.

Recommended Approach: Combine univariable MR (basic causal relationships), multivariable MR (controlling confounders), and mediation MR (causal pathways) with complementary analyses including colocalization, fine-mapping, and experimental validation. Treat MR as contributory evidence, not definitive proof.

Known Limitations

Methodological constraints require careful consideration during interpretation. Key limitations include population stratification differences, shared genetic architecture assumptions, and horizontal pleiotropy vulnerability.

Critical Issues: Sample overlap bias, differential LD patterns across populations, weak instrument bias, inability to model time-varying effects or non-linear relationships, and challenges in detecting pleiotropic effects using summary statistics. Statistical power depends on instrument strength and GWAS sample dimensions.

   Choose exposure data.

 Information for exposure

   Choose mediation data.

 Information for mediation

   Choose outcome data.

 Information for outcome

Step 4. Filter instruments.

   Step 4.1. Genetic variants significantly linked to the exposure/mediation/outcome factor.

   Step 4.2. Perform LD clumping.

   Step 4.3. Calculate R2 and F value.

Exposure

Mediation

Outcome

Step 6. Perform two-sample Mendelian randomization.

   Options for MR analysis.